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27 pages, 42382 KiB

Open AccessArticle

Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids

by Sanghee Lee, Theresa R. Mendoza, Danielle N. Burner, Michelle T. Muldong, Christina C. N. Wu, Catalina Arreola-Villanueva, Abril Zuniga, Olga Greenburg, William Y. Zhu, Jamillah Murtadha, Evodie Koutouan, Naomi Pineda, Hao Pham, Sung-Gu Kang, Hyun Tae Kim, Gabriel Pineda, Kathleen M. Lennon, Nicholas A. Cacalano, Catriona H. M. Jamieson, Christopher J. Kane, Anna A. Kulidjian, Terry Gaasterland and Christina A. M. Jamieson Show full author list Hide full author list

Int. J. Mol. Sci. 2022, 23(6), 3203; https://doi.org/10.3390/ijms23063203 - 16 Mar 2022

Cited by 10 | Viewed by 4960

Abstract

Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, [...] Read more.

Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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16 pages, 3038 KiB

Open AccessArticle

Specific Gut Microbial Environment in Lard Diet-Induced Prostate Cancer Development and Progression

by Hiromi Sato, Shintaro Narita, Masanori Ishida, Yoshiko Takahashi, Huang Mingguo, Soki Kashima, Ryohei Yamamoto, Atsushi Koizumi, Taketoshi Nara, Kazuyuki Numakura, Mitsuru Saito, Toshiaki Yoshioka and Tomonori Habuchi

Int. J. Mol. Sci. 2022, 23(4), 2214; https://doi.org/10.3390/ijms23042214 - 17 Feb 2022

Cited by 7 | Viewed by 2900

Abstract

Lard diet (LD) is a risk factor for prostate cancer (PCa) development and progression. Two immunocompetent mouse models fed with isocaloric specific fat diets (LD) enriched in saturated and monounsaturated fatty acid (SMFA), showed significanftly enhanced PCa progression with weight gain compared with [...] Read more.

Lard diet (LD) is a risk factor for prostate cancer (PCa) development and progression. Two immunocompetent mouse models fed with isocaloric specific fat diets (LD) enriched in saturated and monounsaturated fatty acid (SMFA), showed significanftly enhanced PCa progression with weight gain compared with a fish oil diet (FOD). High gut microbial divergency resulted from difference in diets, and the abundance of several bacterial species, such as in the orders Clostridiales and Lactobacillales, was markedly altered in the feces of LD- or FOD-fed mice. The proportion of the order Lactobacillales in the gut was negatively involved in SMFA-induced body weight gain and PCa progression. We found the modulation of lipid metabolism and cholesterol biosynthesis pathways with three and seven commonly up- and downregulated genes in PCa tissues, and some of them correlated with the abundance of the order Lactobacillales in mouse gut. The expression of sphingosine 1-phosphate receptor 2, which is associated with the order Lactobacillales and cancer progression in mouse models, was inversely associated with aggressive phenotype and weight gain in patients with PCa using the NCBI Gene Expression Omnibus database. Therefore, SMFA may promote PCa progression with the abundance of specific gut microbial species and overexpression of lipogenic genes in PCa. Therapeutics with alteration of gut microbiota and candidate genes involved in diet-induced PCa progression may be attractive in PCa. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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14 pages, 7850 KiB

Open AccessArticle

P-Glycoprotein and Androgen Receptor Expression Reveals Independence of Canine Prostate Cancer from Androgen Hormone Stimulation

by Alexandre Matheus Baesso Cavalca, Andressa Brandi, Ricardo Henrique Fonseca-Alves, Renée Laufer-Amorim and Carlos Eduardo Fonseca-Alves

Int. J. Mol. Sci. 2022, 23(3), 1163; https://doi.org/10.3390/ijms23031163 - 21 Jan 2022

Cited by 3 | Viewed by 2176

Abstract

Canine prostate cancer (PC) is an aggressive disease, and dogs can be considered comparative models for human PC. In recent years, canine PC has been shown to resemble human castrate-resistant prostate cancer. The influx and efflux of testosterone in prostatic luminal cells are [...] Read more.

Canine prostate cancer (PC) is an aggressive disease, and dogs can be considered comparative models for human PC. In recent years, canine PC has been shown to resemble human castrate-resistant prostate cancer. The influx and efflux of testosterone in prostatic luminal cells are regulated by P-glycoprotein (P-gp). Therefore, human PC generally lacks P-gp expression and maintains the expression of androgen receptors (ARs). However, this co-expression has not previously been investigated in dogs. Therefore, this study aimed to evaluate AR and P-gp co-expression to elucidate these protein patterns in canine prostate samples. We identified AR/P-gp double immunofluorescence co-expression of both proteins in normal luminal cells. However, in canine PC, cells lack AR expression and exhibit increased P-gp expression. These results were confirmed by gene expression analyses. Overall, our results strongly suggest that normal canine prostate testosterone influx may be regulated by P-gp expression, and that during progression to PC, prostatic cells lack AR expression and P-gp overexpress. P-gp expression in canine PC may be related to a phenotype of multiple drug resistance. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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14 pages, 2293 KiB

Open AccessArticle

Validation of SV2A-Targeted PET Imaging for Noninvasive Assessment of Neuroendocrine Differentiation in Prostate Cancer

by Bing Guan, Ning Zhou, Cheng-Yang Wu, Songye Li, Yu-An Chen, Sashi Debnath, Mia Hofstad, Shihong Ma, Ganesh V. Raj, Dalin He, Jer-Tsong Hsieh, Yiyun Huang, Guiyang Hao and Xiankai Sun

Int. J. Mol. Sci. 2021, 22(23), 13085; https://doi.org/10.3390/ijms222313085 - 3 Dec 2021

Cited by 12 | Viewed by 3086

Abstract

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) [...] Read more.

Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal variant of prostate cancer (PCa), and it remains a diagnostic challenge. Herein we report our findings of using synaptic vesicle glycoprotein 2 isoform A (SV2A) as a promising marker for positron emission tomography (PET) imaging of neuroendocrine differentiation (NED). The bioinformatic analyses revealed an amplified SV2A gene expression in clinical samples of NEPC versus castration-resistant PCa with adenocarcinoma characteristics (CRPC-Adeno). Importantly, significantly upregulated SV2A protein levels were found in both NEPC cell lines and tumor tissues. PET imaging studies were carried out in NEPC xenograft models with ¹⁸F-SynVesT-1. Although ¹⁸F-SynVesT-1 is not a cancer imaging agent, it showed a significant uptake level in the SV2A⁺ tumor (NCI-H660: 0.70 ± 0.14 %ID/g at 50–60 min p.i.). The SV2A blockade resulted in a significant reduction of tumor uptake (0.25 ± 0.03 %ID/g, p = 0.025), indicating the desired SV2A imaging specificity. Moreover, the comparative PET imaging study showed that the DU145 tumors could be clearly visualized by ¹⁸F-SynVesT-1 but not ⁶⁸Ga-PSMA-11 nor ⁶⁸Ga-DOTATATE, further validating the role of SV2A-targeted imaging for noninvasive assessment of NED in PCa. In conclusion, we demonstrated that SV2A, highly expressed in NEPC, can serve as a promising target for noninvasive imaging evaluation of NED. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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11 pages, 2834 KiB

Open AccessArticle

Optimization of Apta-Sensing Platform for Detection of Prostate Cancer Marker PCA3

by Sarra Takita, Alexei Nabok, Anna Lishchuk and David Smith

Int. J. Mol. Sci. 2021, 22(23), 12701; https://doi.org/10.3390/ijms222312701 - 24 Nov 2021

Cited by 6 | Viewed by 3072

Abstract

This work is a continuation of our research into the development of simple, reliable, and cost-effective methods for the early diagnosis of prostate cancer (PCa). The proposed method is based on the electrochemical detection of the PCA3 biomarker of PCa (long non-coded RNA [...] Read more.

This work is a continuation of our research into the development of simple, reliable, and cost-effective methods for the early diagnosis of prostate cancer (PCa). The proposed method is based on the electrochemical detection of the PCA3 biomarker of PCa (long non-coded RNA transcript expressed in urine) using a specific aptamer labeled with a redox group (methylene blue). The electrochemical measurements (cyclic voltammograms) obtained from electrodes functionalized with the aptamer were complemented in this work by another biosensing technique: total internal reflection ellipsometry (TIRE). In addition to proving the concept of the detection of PCA3 in low concentrations down to 90 pM, this study improved our understanding of the processes by which PCA3 binds to its specific aptamer. The high specificity of the binding of PCA3 to the aptamer was assessed by studying the binding kinetics, which yielded an affinity constant (K_D) of 2.58 × 10⁻⁹ M. Additional XPS measurements confirmed the strong covalent binding of aptamers to gold and showed spectral features associated with PCA3 to aptamer binding. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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23 pages, 10720 KiB

Open AccessArticle

Synergistic Interaction of CPP2 Coupled with Thiazole Derivates Combined with Clotrimazole and Antineoplastic Drugs in Prostate and Colon Cancer Cell Lines

by Diana Duarte and Nuno Vale

Int. J. Mol. Sci. 2021, 22(21), 11984; https://doi.org/10.3390/ijms222111984 - 5 Nov 2021

Cited by 7 | Viewed by 2571

Abstract

Cell-penetrating peptides (CPPs) are small peptide sequences used mainly as cellular delivery agents that are able to efficiently deliver cargo into cells. Some CPPs also demonstrate intrinsic anticancer properties. Previously, our group developed a new family of CPP2-thiazole conjugates that have been shown [...] Read more.

Cell-penetrating peptides (CPPs) are small peptide sequences used mainly as cellular delivery agents that are able to efficiently deliver cargo into cells. Some CPPs also demonstrate intrinsic anticancer properties. Previously, our group developed a new family of CPP2-thiazole conjugates that have been shown to effectively reduce the proliferation of different cancer cells. This work aimed to combine these CPP2-thiazole conjugates with paclitaxel (PTX) and 5-fluorouracil (5-FU) in PC-3 prostate and HT-29 colon cancer cells, respectively, to evaluate the cytotoxic effects of these combinations. We also combined these CPP2-thiazole conjugates with clotrimazole (CLZ), an antifungal agent that has been shown to decrease cancer cell proliferation. Cell viability was evaluated using MTT and SRB assays. Drug interaction was quantified using the Chou–Talalay method. We determined that CPP2 did not have significant activity in these cells and demonstrate that N-terminal modification of this peptide enhanced its anticancer activity in both cell lines. Our results also showed an uneven response between cell lines to the proposed combinations. PC-3 cells were more responsive to the combination of CPP2-thiazole conjugates with CLZ than PTX and were more sensitive to these combinations than HT-29 cells. In addition, the interaction of drugs resulted in more synergism in PC-3 cells. These results suggest that N-terminal modification of CPP2 results in the enhanced anticancer activity of the peptide and demonstrates the potential of CPPs as adjuvants in cancer therapy. These results also validate that CLZ has significant anticancer activity both alone and in combination and support the strategy of drug repurposing coupled to drug combination for prostate cancer therapy. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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21 pages, 6571 KiB

Open AccessArticle

Atorvastatin Modulates the Efficacy of Electroporation and Calcium Electrochemotherapy

by Wojciech Szlasa, Aleksander Kiełbik, Anna Szewczyk, Vitalij Novickij, Mounir Tarek, Zofia Łapińska, Jolanta Saczko, Julita Kulbacka and Nina Rembiałkowska

Int. J. Mol. Sci. 2021, 22(20), 11245; https://doi.org/10.3390/ijms222011245 - 18 Oct 2021

Cited by 8 | Viewed by 3240

Abstract

Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is eventually affected by the organization of actin fibers. Atorvastatin is a statin known to influence both the cholesterol [...] Read more.

Electroporation is influenced by the features of the targeted cell membranes, e.g., the cholesterol content and the surface tension of the membrane. The latter is eventually affected by the organization of actin fibers. Atorvastatin is a statin known to influence both the cholesterol content and the organization of actin. This work analyzes the effects of the latter on the efficacy of electroporation of cancer cells. In addition, herein, electroporation was combined with calcium chloride (CaEP) to assess as well the effects of the statin on the efficacy of electrochemotherapy. Cholesterol-rich cell lines MDA-MB231, DU 145, and A375 underwent (1) 48 h preincubation or (2) direct treatment with 50 nM atorvastatin. We studied the impact of the statin on cholesterol and actin fiber organization and analyzed the cells’ membrane permeability. The viability of cells subjected to PEF (pulsed electric field) treatments and CaEP with 5 mM CaCl₂ was examined. Finally, to assess the safety of the therapy, we analyzed the N-and E-cadherin localization using confocal laser microscopy. The results of our investigation revealed that depending on the cell line, atorvastatin preincubation decreases the total cholesterol in the steroidogenic cells and induces reorganization of actin nearby the cell membrane. Under low voltage PEFs, actin reorganization is responsible for the increase in the electroporation threshold. However, when subject to high voltage PEF, the lipid composition of the cell membrane becomes the regulatory factor. Namely, preincubation with atorvastatin reduces the cytotoxic effect of low voltage pulses and enhances the cytotoxicity and cellular changes induced by high voltage pulses. The study confirms that the surface tension regulates of membrane permeability under low voltage PEF treatment. Accordingly, to reduce the unfavorable effects of preincubation with atorvastatin, electroporation of steroidogenic cells should be performed at high voltage and combined with a calcium supply. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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Review

Jump to: Research

17 pages, 1350 KiB

Open AccessReview

The Crosstalk of Long Non-Coding RNA and MicroRNA in Castration-Resistant and Neuroendocrine Prostate Cancer: Their Interaction and Clinical Importance

by Che-Yuan Hu, Kuan-Yu Wu, Tsung-Yen Lin and Chien-Chin Chen

Int. J. Mol. Sci. 2022, 23(1), 392; https://doi.org/10.3390/ijms23010392 - 30 Dec 2021

Cited by 18 | Viewed by 3249

Abstract

Prostate cancer is featured by its heterogeneous nature, which indicates a different prognosis. Castration-resistant prostate cancer (CRPC) is a hallmark of the treatment-refractory stage, and the median survival of patients is only within two years. Neuroendocrine prostate cancer (NEPC) is an aggressive variant [...] Read more.

Prostate cancer is featured by its heterogeneous nature, which indicates a different prognosis. Castration-resistant prostate cancer (CRPC) is a hallmark of the treatment-refractory stage, and the median survival of patients is only within two years. Neuroendocrine prostate cancer (NEPC) is an aggressive variant that arises from de novo presentation of small cell carcinoma or treatment-related transformation with a median survival of 1–2 years from the time of diagnosis. The epigenetic regulators, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been proven involved in multiple pathologic mechanisms of CRPC and NEPC. LncRNAs can act as competing endogenous RNAs to sponge miRNAs that would inhibit the expression of their targets. After that, miRNAs interact with the 3’ untranslated region (UTR) of target mRNAs to repress the step of translation. These interactions may modulate gene expression and influence cancer development and progression. Otherwise, epigenetic regulators and genetic mutation also promote neuroendocrine differentiation and cancer stem-like cell formation. This step may induce neuroendocrine prostate cancer development. This review aims to provide an integrated, synthesized overview under current evidence to elucidate the crosstalk of lncRNAs with miRNAs and their influence on castration resistance or neuroendocrine differentiation of prostate cancer. Notably, we also discuss the mechanisms of lncRNA–miRNA interaction in androgen receptor-independent prostate cancer, such as growth factors, oncogenic signaling pathways, cell cycle dysregulation, and cytokines or other transmembrane proteins. Conclusively, we underscore the potential of these communications as potential therapeutic targets in the future. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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20 pages, 14525 KiB

Open AccessReview

An Insight on Novel Molecular Pathways in Metastatic Prostate Cancer: A Focus on DDR, MSI and AKT

by Veronica Mollica, Andrea Marchetti, Matteo Rosellini, Giacomo Nuvola, Alessandro Rizzo, Matteo Santoni, Alessia Cimadamore, Rodolfo Montironi and Francesco Massari

Int. J. Mol. Sci. 2021, 22(24), 13519; https://doi.org/10.3390/ijms222413519 - 16 Dec 2021

Cited by 15 | Viewed by 3552

Abstract

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment [...] Read more.

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment approaches. Genomic profiling has evidenced that DNA damage repair genes’ alterations are quite frequent in metastatic, castration resistant prostate cancer and specific therapies can interfere with this pathway, showing promising activity in this setting. Microsatellite instability is gaining attention as it seems to represent a predictive factor of the response to immunotherapy. Furthermore, the PTEN-PI3K-AKT pathway is another possible treatment target being investigated. In this review, we explore the current knowledge on these frequent genomic alterations of metastatic prostate cancer, their possible therapeutic repercussions and the promising future treatments under evaluation. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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12 pages, 944 KiB

Open AccessReview

Genomic Features and Clinical Implications of Intraductal Carcinoma of the Prostate

by Minyong Kang, Hyunwoo Lee, Sun-Ju Byeon, Ghee Young Kwon and Seong Soo Jeon

Int. J. Mol. Sci. 2021, 22(23), 13125; https://doi.org/10.3390/ijms222313125 - 4 Dec 2021

Cited by 8 | Viewed by 2816

Abstract

Intraductal carcinoma of the prostate (IDC-P) is a rare and unique form of aggressive prostate carcinoma, which is characterized by an expansile proliferation of malignant prostatic epithelial cells within prostatic ducts or acini and the preservation of basal cell layers around the involved [...] Read more.

Intraductal carcinoma of the prostate (IDC-P) is a rare and unique form of aggressive prostate carcinoma, which is characterized by an expansile proliferation of malignant prostatic epithelial cells within prostatic ducts or acini and the preservation of basal cell layers around the involved glands. The vast majority of IDC-P tumors result from adjacent high-grade invasive cancer via the retrograde spreading of tumor cells into normal prostatic ducts or acini. A subset of IDC-P tumors is rarely derived from the de novo intraductal proliferation of premalignant cells. The presence of IDC-P in biopsy or surgical specimens is significantly associated with aggressive pathologic features, such as high Gleason grade, large tumor volume, and advanced tumor stage, and with poor clinical courses, including earlier biochemical recurrence, distant metastasis, and worse survival outcomes. These architectural and behavioral features of IDC-P may be driven by specific molecular properties. Notably, IDC-P possesses distinct genomic profiles, including higher rates of TMPRSS2–ERG gene fusions and PTEN loss, increased percentage of genomic instability, and higher prevalence of germline BRCA2 mutations. Considering that IDC-P tumors are usually resistant to conventional therapies for prostate cancer, further studies should be performed to develop optimal therapeutic strategies based on distinct genomic features, such as treatment with immune checkpoint blockades or poly (adenosine diphosphate–ribose) polymerase inhibitors for patients harboring increased genomic instability or BRCA2 mutations, as well as genetic counseling with genetic testing. Patient-derived xenografts and tumor organoid models can be the promising in vitro platforms for investigating the molecular features of IDC-P tumor. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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15 pages, 1626 KiB

Open AccessReview

Delineating the Molecular Events Underlying Development of Prostate Cancer Variants with Neuroendocrine/Small Cell Carcinoma Characteristics

by Mayuko Kanayama and Jun Luo

Int. J. Mol. Sci. 2021, 22(23), 12742; https://doi.org/10.3390/ijms222312742 - 25 Nov 2021

Cited by 5 | Viewed by 2893

Abstract

The treatment landscape of prostate cancer has changed dramatically following the advent of novel systemic therapies, most of which target the androgen receptor (AR). Agents such as abiraterone, enzalutamide, apalutamide, darolutamide were designed to further suppress androgen receptor signaling following gonadal suppression achieved [...] Read more.

The treatment landscape of prostate cancer has changed dramatically following the advent of novel systemic therapies, most of which target the androgen receptor (AR). Agents such as abiraterone, enzalutamide, apalutamide, darolutamide were designed to further suppress androgen receptor signaling following gonadal suppression achieved by first-line androgen deprivation therapies. These potent AR targeting agents are increasingly used in the earlier stages of the disease spectrum with the goal of delaying disease progression and extending survival. Although these therapies are effective in controlling prostate tumors dependent on or addicted to AR signaling, prostate tumors surviving the onslaught of potent treatments may evolve and develop drug resistance. A substantial proportion of treatment failures can be explained by the development of treatment-induced aggressive prostate cancer variants such as neuroendocrine/small cell carcinoma. These emerging disease entities demand detailed characterization and precise definitions. We postulate that these treatment-induced prostate cancer entities should be defined molecularly to overcome the drawbacks associated with the current clinical and pathological definitions. A precise molecular definition conforms with current knowledge on the molecular evolution of this disease entity and will enable early detection and early intervention. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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25 pages, 2054 KiB

Open AccessReview

Role of PI3K-AKT-mTOR Pathway as a Pro-Survival Signaling and Resistance-Mediating Mechanism to Therapy of Prostate Cancer

by Thanakorn Pungsrinont, Julia Kallenbach and Aria Baniahmad

Int. J. Mol. Sci. 2021, 22(20), 11088; https://doi.org/10.3390/ijms222011088 - 14 Oct 2021

Cited by 93 | Viewed by 7879

Abstract

Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeted therapy are the gold standard options for treating prostate cancer (PCa). These are initially effective, as localized and the early stage of metastatic disease are androgen- and castration-sensitive. The tumor strongly relies on systemic/circulating androgens [...] Read more.

Androgen deprivation therapy (ADT) and androgen receptor (AR)-targeted therapy are the gold standard options for treating prostate cancer (PCa). These are initially effective, as localized and the early stage of metastatic disease are androgen- and castration-sensitive. The tumor strongly relies on systemic/circulating androgens for activating AR signaling to stimulate growth and progression. However, after a certain point, the tumor will eventually develop a resistant stage, where ADT and AR antagonists are no longer effective. Mechanistically, it seems that the tumor becomes more aggressive through adaptive responses, relies more on alternative activated pathways, and is less dependent on AR signaling. This includes hyperactivation of PI3K-AKT-mTOR pathway, which is a central signal that regulates cell pro-survival/anti-apoptotic pathways, thus, compensating the blockade of AR signaling. The PI3K-AKT-mTOR pathway is well-documented for its crosstalk between genomic and non-genomic AR signaling, as well as other signaling cascades. Such a reciprocal feedback loop makes it more complicated to target individual factor/signaling for treating PCa. Here, we highlight the role of PI3K-AKT-mTOR signaling as a resistance mechanism for PCa therapy and illustrate the transition of prostate tumor from AR signaling-dependent to PI3K-AKT-mTOR pathway-dependent. Moreover, therapeutic strategies with inhibitors targeting the PI3K-AKT-mTOR signal used in clinic and ongoing clinical trials are discussed. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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14 pages, 1093 KiB

Open AccessReview

Exosomes as A Next-Generation Diagnostic and Therapeutic Tool in Prostate Cancer

by Simita Gaglani, Edgar Gonzalez-Kozlova, Dara J. Lundon, Ashutosh K. Tewari, Navneet Dogra and Natasha Kyprianou

Int. J. Mol. Sci. 2021, 22(18), 10131; https://doi.org/10.3390/ijms221810131 - 20 Sep 2021

Cited by 26 | Viewed by 3941

Abstract

Extracellular vesicles (EVs) have brought great momentum to the non-invasive liquid biopsy procedure for the detection, characterization, and monitoring of cancer. Despite the common use of PSA (prostate-specific antigen) as a biomarker for prostate cancer, there is an unmet need for a more [...] Read more.

Extracellular vesicles (EVs) have brought great momentum to the non-invasive liquid biopsy procedure for the detection, characterization, and monitoring of cancer. Despite the common use of PSA (prostate-specific antigen) as a biomarker for prostate cancer, there is an unmet need for a more specific diagnostic tool to detect tumor progression and recurrence. Exosomes, which are EVs that are released from all cells, play a large role in physiology and pathology, including cancer. They are involved in intercellular communication, immune function, and they are present in every bodily fluid studied—making them an excellent window into how cells are operating. With liquid biopsy, EVs can be isolated and analyzed, enabling an insight into a potential therapeutic value, serving as a vehicle for drugs or nucleic acids that have anti-neoplastic effects. The current application of advanced technology also points to higher-sensitivity detection methods that are minimally invasive. In this review, we discuss the current understanding of the significance of exosomes in prostate cancer and the potential diagnostic value of these EVs in disease progression. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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26 pages, 683 KiB

Open AccessReview

Prostate Cancer Radiogenomics—From Imaging to Molecular Characterization

by Matteo Ferro, Ottavio de Cobelli, Mihai Dorin Vartolomei, Giuseppe Lucarelli, Felice Crocetto, Biagio Barone, Alessandro Sciarra, Francesco Del Giudice, Matteo Muto, Martina Maggi, Giuseppe Carrieri, Gian Maria Busetto, Ugo Falagario, Daniela Terracciano, Luigi Cormio, Gennaro Musi and Octavian Sabin Tataru

Int. J. Mol. Sci. 2021, 22(18), 9971; https://doi.org/10.3390/ijms22189971 - 15 Sep 2021

Cited by 61 | Viewed by 5810

Abstract

Radiomics and genomics represent two of the most promising fields of cancer research, designed to improve the risk stratification and disease management of patients with prostate cancer (PCa). Radiomics involves a conversion of imaging derivate quantitative features using manual or automated algorithms, enhancing [...] Read more.

Radiomics and genomics represent two of the most promising fields of cancer research, designed to improve the risk stratification and disease management of patients with prostate cancer (PCa). Radiomics involves a conversion of imaging derivate quantitative features using manual or automated algorithms, enhancing existing data through mathematical analysis. This could increase the clinical value in PCa management. To extract features from imaging methods such as magnetic resonance imaging (MRI), the empiric nature of the analysis using machine learning and artificial intelligence could help make the best clinical decisions. Genomics information can be explained or decoded by radiomics. The development of methodologies can create more-efficient predictive models and can better characterize the molecular features of PCa. Additionally, the identification of new imaging biomarkers can overcome the known heterogeneity of PCa, by non-invasive radiological assessment of the whole specific organ. In the future, the validation of recent findings, in large, randomized cohorts of PCa patients, can establish the role of radiogenomics. Briefly, we aimed to review the current literature of highly quantitative and qualitative results from well-designed studies for the diagnoses, treatment, and follow-up of prostate cancer, based on radiomics, genomics and radiogenomics research. Full article

(This article belongs to the Special Issue Molecular Advances in Prostate Cancer)

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